ABSTRACT Mammalian development involves a number of finely-tuned, time-sensitive molecular and cellular processes essential to ensure normal physiology and health later in life. Disruptions during this critical period may lead to impaired viability, congenital abnormalities and associated morbidities. In humans, the causes of many congenital abnormalities remain unidentified, hampering efforts for their prevention. These may include most cases of cardiomyopathies, hydrocephalus, Chiari malformations, cleft palate, choanal atresia and other cranio-encephalic dysmorphisms. We propose that transient, unidentified fetal thyrotoxicosis (i.e., thyroid hormone excess) causes some of these abnormalities. Fetal thyrotoxicosis may occur as a result of exposure to chemicals that act as endocrine disruptors, secondary to maternal thyroid disease before clinical treatment is initiated, or as a consequence of environmentally-driven epigenetic disregulation in the gene (Dio3) that maintains developmental levels of thyroid hormone levels much lower than those in the maternal circulation in order to prevent untimely exposure. Using a highly suitable mouse model of fetal thyrotoxicosis based on a genetic or epigenetic deficiency in DIO3, we propose to characterize the extent and ontogeny of cranio-encephalic and cardiac abnormalities that arise as a consequence of thyroid hormone excess during development (Aim 1). We also propose to identify the molecular mechanisms underlying the generation of those congenital abnormalities (Aim 2). We anticipate that our work will demonstrate that fetal thyrotoxicosis is a novel factor contributing to the generation of congenital abnormalities currently considered idiopathic, shedding important light into their etiology. This project will increase the appreciation of the potential risks of fetal thyrotoxicosis early in development and encourage close assessment of thyroid conditions and adequate clinical interventions in pregnant women and prospective mothers to better prevent congenital malformations. We also anticipate obtaining novel insight into the sensitive time frames and the responsible underlying molecular mechanisms by which thyroid hormone excess causes these abnormalities. This will open new avenues of research and inform future studies.